The use of macrolides for various infectious diseases is well known. Erythromycin was the first compound of this class to be introduced into clinical practice. Since then, additional macrolides, including ketolides have garnered much attention for their ability to treat a wide range of disease states. In particular, macrolides are an important component of therapies for treating bacterial, protozoal, and viral infections. In addition, macrolides are often used in patients allergic to penicillins.
Illustrative of their wide ranging uses, macrolide compounds have been found to be effective for the treatment and prevention of infections caused by a broad spectrum of bacterial and protozoal infections. They are also useful for infections of respiratory tract and soft tissue infections. Macrolide antibiotics are found to be effective on beta-hemolytic streptococci, pneumococci, staphylococci and enterococci. They are also found to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia.
Macrolide compounds are characterized by the presence of a large lactone ring, which is generally a 14, 15, or 16-membered macrocyclic lactone, to which one or more saccharides, including deoxy sugars such as cladinose and desosamine, may be attached. For example, erythromycin is a 14-membered macrolide that includes two sugar moieties. Spiramycin belongs to a second generation of macrolide compounds that include a 16-membered ring. Third generation macrolide compounds include for example semi-synthetic derivatives of erythromycin A, such as azithromycin and clarithromycin. Finally, ketolides represent a newer class of macrolide antibiotics that have received much attention recently due to their acid stability, and most importantly due to their excellent activity against organisms that are resistant to other macrolides. Like erythromycins, ketolides are 14-membered ring macrolide derivatives characterized by a keto group at the C-3 position (Curr. Med. Chem., “Anti-Infective Agents,” 1:15-34 (2002)). Several ketolide compounds are currently under clinical investigation; however, telithromycin (U.S. Pat. No. 5,635,485) is the first compound in this family to be approved for use.
Liang et al. in U.S. Patent Appl. Pub. No. 2006/0100164, the disclosure of which is incorporated herein by reference, describes a new series of compounds, and an illustrative synthesis thereof. These new compounds show excellent activity against pathogenic organisms, including those that have already exhibited resistance to current therapies. In particular, Liang et al. describes compounds including those of formula (I):
and pharmaceutically acceptable salts, solvates, and hydrates thereof; wherein
R1 is a monosaccharide or polysaccharide;
A is —CH2—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2-, —S(O)2NH—, —C(O)NHS(O)2-;
B is —(CH2)n— where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons, which may contain any alkenyl or alkynyl group;
C represents 1 or 2 substituents independently selected in each instance from hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted;
V is —C(O)—, —C(═NR11)—, —CH(NR12R13)—, or —N(R14)CH2—; where R11 is hydroxy or alkoxy, R12 and R13 are each independently selected from hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; and R14 is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl;
W is hydrogen, F, Cl, Br, I, or OH; and
X is hydrogen; and Y is OR7; where R7 is hydrogen, a monosaccharide or disaccharide, including aminosugars or halosugars, alkyl, aryl, heteroaryl, acyl, such as 4-nitro-phenylacetyl and 2-pyridylacetyl, or —C(O)NR8R9, where R8 and R9 are each independently selected from hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; or X and Y taken together with the attached carbon to form C═O.
In particular, the compound 11-N-[[4-(3-aminophenyl)-1,2,3-triazol-1-yl]-butyl]-5-desosaminyl-2-fluoro-3-oxoerythronolide A, 11,12-cyclic carbamate is described by Liang et al.
Due to the importance of these new compounds and others that are being used to provide beneficial therapies for the treatment of pathogenic organisms, alternative and/or improved processes for preparing these compounds are needed.
For example, the inventors hereof have discovered that side-reactions occur, and undesirable side-products and impurities are formed using the conventional synthesis of compounds of formula (I). Those side-reactions decrease the overall yield of the desired compounds, and those side-products and impurities may complicate the purification of the desired compounds. Described herein are new processes that may be advantageous in preparing compounds of formula (I) that avoid such side-products, and/or may be purified to higher levels of purity.